Abstract
Purpose. Population-based studies on cervical cancer providing survival estimates by age, histology, and stage have been sparse. We aimed to derive most up-to-date and detailed survival estimates for cervical cancer patients in Germany. Methods. We used a pooled German national dataset including data from 11 cancer registries covering a population of 33 million people. Included were 15 685 patients diagnosed with cervical cancer from 1997 to 2006. Period analysis was performed to calculate the five-year relative survival (RS) 2002–2006. Trends in survival between 2002 and 2006 were examined using model-based period analysis. Age-adjustment was done using five age groups (15–44, 45–54, 55–64, 65–74, and 75 + years). Results. Overall, age-adjusted five-year relative survival in 2002–2006 was 64.7%. A strong age gradient was observed, with five-year RS decreasing from 81.7% in age group 15–49 years to 46.3% in age group 70 + years. Prognosis furthermore strongly varied by stage, with age-adjusted five-year RS reaching 84.6% for localized, 48.2% for regional, and 17.9% for distant stage. From 2002 to 2006, a significant improvement (4.7 percent units) in overall age-adjusted five-year RS was seen. The improvement was most pronounced for age groups 55–64 years (from 54.2 to 65.6%) and 65–74 years (from 50.0 to 58.1%). Conclusion. In this first comprehensive population-based study from Germany, prognosis of cervical cancer strongly varied by age and stage. Prognosis continued to improve, in particular in age range 55–74 years, in the five-year period assessed.
According to estimates by the International Agency for Research on Cancer (IARC) [Citation1], cervical cancer (cancer of the cervix uteri) ranks as the 3rd most common cancer in women worldwide (behind breast and colorectal cancer) with 529 000 new cases diagnosed in 2008. It is furthermore the most common cause of gynecologic cancer death globally with 274 000 deaths in 2008. Widespread screening for cervical cancer with detection and removal of premalignant lesions has dramatically reduced the incidence and mortality of cervical cancer in developed countries [Citation2–5]. In Germany, cervical cancer has become a rare cancer, with only 4440 new cases and 2018 deaths in 2008 [Citation6], even though the decline in incidence and mortality has been less pronounced than in other European countries [Citation3,Citation4,Citation7,Citation8], probably due to offer of screening (which was introduced in 1971) in an opportunistic rather than organized manner [Citation9,Citation10].
Five-year relative survival (RS) of cervical cancer patients in Europe has reached roughly 60–65% [Citation11,Citation12]. However, available data mostly pertain to patients diagnosed in the 1990s. Previous population-based data from Germany mostly relied on the Saarland Cancer Registry, covering only 1.3% of the total German population [Citation13]. Also, population-based survival data by stage, the key prognostic factor for cancer patients, have been sparse.
In this article we provide detailed (stratified by age, histology, and stage) population-based survival estimates of cervical cancer patients in Germany based on a pooled German national database from 11 population-based cancer registries, covering 33 million inhabitants. We employed standard and model-based period analysis [Citation14–17] to derive up-to-date estimates and recent trends in survival of cervical cancer patients in the early 21st century.
Material and methods
Database
This analysis is based on a pooled German national dataset described in detail previously [Citation18]. Briefly, data from 11 German cancer registries (covering a population of 33 million residents, i.e. 40% of the German population) with estimated completeness > 90% in the period 2004–2006 were combined. Patients aged 15 years or older and diagnosed with malignant tumors during 1997–2006 were included. Some registries provided only patients diagnosed in more recent years (Bremen: 1998–2006; Schleswig-Holstein: 1999–2006; Lower Saxony: 2001–2006; Bavaria: 2002–2006). However, sensitivity analyses excluding these registries yielded very similar results, and results are therefore shown for all registries combined throughout. Follow-up with respect to vital status was performed until 2004 in North Rhine-Westphalia and until the end of 2006 in all other registries.
The current analysis focuses on patients diagnosed with cervical cancer (ICD-10 code: C53). According to the International Classification of Diseases for Oncology (ICD-O-3) [Citation19] and the Surveillance, Epidemiology and End Results (SEER) Survival Monograph published in 2007 [Citation20], cancers were grouped into five major histologic groups: squamous cell, adenocarcinoma, adenosquamous, carcinoma not otherwise specified (NOS), and others (mixture). Squamous cell carcinomas were further divided into four subtypes (keratinizing, non-keratinizing, microinvasive, and other squamous). For more details about histology and morphology codes and their frequencies in the analyzed dataset please refer to the Appendix (Supplementary Appendix to be found online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2012.708105).
Staging was built by transformation the TNM information [Citation21], using a variable indicating grouped clinical stage with four categories, i.e. localized (T0/1/2N0M0), regional (T3/4N0M0 or any TN + M0), distant (any T any NM +), and unknown.
Statistical analysis
Period analysis [Citation14,Citation15] was used to derive five-year relative survival (RS) estimates for 2002–2006. Period analysis provides more up-to-date survival estimates than traditional cohort-based survival analysis by focusing exclusively on survival experience during the most recent time period for which data are available. This is achieved by left truncation of observations at the beginning of the period of interest in addition to right censoring of observations at its end. It has been shown by extensive empirical evaluations that period estimates of five-year survival for a specific period closely predict five-year survival later observed for patients diagnosed in that period [Citation22,Citation23]. Relative survival was calculated as the ratio of the observed survival in the group of cervical cancer patients divided by the expected survival of a comparable group from general population [Citation24]. Expected survival was derived from life tables for the population of Germany stratified by age, sex, calendar period and federal states, using the Ederer II method [Citation25].
Five-year RS was calculated by histologic subtypes for three major age groups (15–49, 50–69, and 70 + years) in analogy with the SEER Survival Monograph published in 2007 [Citation20]. In addition, age-adjusted five-year RS was calculated for patient subgroups defined by histology and stage. RS estimates were not reported if the standard errors exceeded 5 percent units. Age-adjustment for standard period analysis was done by deriving weighted averages of age-specific five-year RS estimates, using weights of five age groups (15–44, 45–54, 55–64, 65–74, and 75 + years) according to the International Cancer Survival Standards [Citation26].
In addition to “standard” period analysis [Citation15], model-based period analysis [Citation16,Citation17] was employed to assess recent trends within the 2002–2006 period. An advantage to computing simple period analysis estimates for single calendar years is the increased precision of model-based period estimates, which results from the use of the whole data set in the estimation of the survival estimates for 2002 and 2006. In addition, model-based period analysis allows the significance of time trends to be tested. Model-based period analysis is based on a Poisson regression model. Age group-specific numbers of patients at risk and of deaths by year of follow-up for each single calendar year between 2002 and 2006 were computed. The numbers of death were then modeled as a function of the year of follow-up (entered as a categorical variable) and the calendar year (added as continuous variable) by Poisson regression with the logarithm of the person-years at risk as offset [Citation16,Citation17]. Separate models were run by age groups and major histological groups. Model-based estimates of five-year RS for the first (2002) and last year (2006) of the period and a p-value for the linear trend in RS between 2002 and 2006 (i.e. the p-value for the linear variable calendar year) were derived. Statistical significance for trend tests was defined by two-sided p < 0.05. Standard errors of the model-based five-year RS estimates were calculated using the delta method as previously described [Citation16].
All calculations were performed with the SAS statistical software package (version 9.2, SAS Institute Inc., Cary, North Carolina, USA), using special macros for the period analysis as described in detail elsewhere [Citation16,Citation27].
Results
The basic characteristics of the dataset used in the current period analysis for cervical cancer patients diagnosed in Germany from 1997 to 2006 are presented in . After exclusion of 1315 patients (7.7%) notified by death certificate only (DCO) or by autopsy only, and three patients without dates of diagnosis or death, 15 685 cases with a median age at diagnosis of 51 years were included in the analysis. 98% of these cases were microscopically confirmed.
Table I. Description of the dataset used in period survival analysis for cervical cancer patients diagnosed in Germany, 1997–2006.
Age-adjusted and age group-specific five-year RS estimates for the time period 2002–2006 by histology are presented in . Overall, age-adjusted five-year RS in 2002–2006 was 64.7%. Prognosis varied strongly by histology, with age-adjusted five-year RS ranging from 53.4% (carcinoma NOS) to 99.2% (microinvasive squamous cell carcinoma), though those two subtypes had very small numbers of cases. Prognosis in squamous cell carcinomas was slightly higher than in adenocarcinomas, with age-adjusted five-year RS estimates reaching 66.4% and 63.3%, respectively. Overall, a strong age gradient was observed, with five-year RS decreasing from 81.7% in the age group 15–49 years to 46.3% in the age group 70 + years. The strong age gradient was consistently seen within major histologic subtypes, except for microinvasive carcinomas with five-year RS estimates > 95% even in the age group 50–69 years.
Table II. Age-adjusted and age group-specific 5-year relative survival (RS) for the period 2002–2006 by histologic subtypes of cervical cancer patients diagnosed in Germany, 1997–2006a.
shows age-adjusted five-year RS by histology and stage. Among the restricted dataset with complete information on stage (7968 cases, representing 51% of included cases), 60% of cases were diagnosed at localized stage. Overall, prognosis strongly varied by stage, with age-adjusted five-year RS reaching 84.6% for localized, 48.2% for regional, and 17.9% for distant stage. The strong gradient in prognosis by tumor stage was consistently seen for squamous cell cancer and adenocarcinomas. Patients with stage information were on average 3.4 years younger and had a slightly higher age-adjusted survival than those without stage information [65.3 (0.9) vs. 64.4 (0.8)].
Table III. Age-adjusted 5-year relative survival (RS) for the period 2002–2006 by histologic subtypes and stage for cervical cancer patients diagnosed in Germany, 1997–2006a.
shows model-based age group-specific five-year RS estimates for 2002 and 2006. Overall, there was a substantial improvement in prognosis between 2002 and 2006, with age-adjusted five-year RS estimates increasing from 61.9% in 2002 to 66.6% in 2006 (increase by 4.7 percent units, p = 0.002). The improvement in survival was consistently seen for all age subgroups, even though the improvement was most pronounced for age groups 55–64 and 65–74 years, with five-year RS increasing from 54.2% to 65.6% and from 50.0% to 58.1%, respectively, and statistically significant in the age group 50–64 years only (p = 0.004).
Table IV. Model-based age group-specific 5-year relative survival (RS) in 2002 and 2006 for cervical cancer patients diagnosed in Germany, 1997–2006*.
shows model-based age-adjusted five-year RS estimates in 2002 and 2006 by histology and stage. For the five-year period between 2002 and 2006, an improvement of similar magnitude was seen for both squamous cell carcinomas and adenocarcinomas, even though the improvement was not statistically significant for the latter, much smaller group of patients. Whereas no improvement in prognosis was seen for patients with localized cancer, five-year RS substantially increased for patients with regional and distant tumor spread, but again these increases did not reach statistical significance in stage specific analyses.
Table V. Model-based age-adjusted 5-year relative survival in 2002 and 2006 by histology and stage for cervical cancer patients diagnosed in Germany, 1997–2006*.
Discussion
In this manuscript we provide the first comprehensive population-based analysis of survival of patients with cervical cancer from Germany available to date. Overall, age-adjusted five-year relative survival from 2002 to 2006 was 64.7%. A strong age gradient was observed, with five-year RS decreasing from 81.7% in age group 15–49 years to 46.3% in age group 70 + years. Prognosis furthermore strongly varied by stage, with age-adjusted five-year RS reaching 84.6% for localized, 48.2% for regional, and 17.9% for distant stage. For the recent five-year period under investigation, a statistically significant improvement in overall age-adjusted five-year relative survival estimates (elevation of 4.7 percent units) was seen, the improvement being most pronounced in the age range 55–74 years.
Previous analyses of trends in five-year RS of patients with cervical cancer in Europe had revealed an increase by three percent units in 1978–89 [Citation28], by two percent units in 1983–94 [Citation29], and by 1.3 percent units in 1988–99 [Citation30]. The statistically significant 4.7% increase in overall age-adjusted five-year RS estimates over 2002–2006 suggests that the steady but slow improvement in five-year RS previously observed in European countries may have continued and accelerated in recent years in Germany, where survival of patients with cervical cancer had been slightly below the European average in the past [Citation11].
Although the reasons for the increase in survival from 2002 to 2006 are difficult to judge in the absence of detailed data on diagnosis and treatment, it seems unlikely that diagnosis and screening (which had been in place and remained essentially unchanged in Germany for several decades) have made major contributions. Furthermore, the stage distribution did not change during the period of investigation, and survival of localized cases remained stable. These findings are not in favor of early diagnosis or stage migration effects. A more plausible explanation might be changes in treatment. A major change in standard treatment of cervical cancer occurred in 1999, when the US National Cancer Institute (NCI) proposed that “concomitant chemoradiotherapy should be considered instead of radiotherapy alone in women with cervical cancer”. Thereafter the recommendation has been adopted quickly and widely in clinical practice, resulting in improved overall, disease-free and progression-free survival [Citation31,Citation32]. Initially, concurrent chemoradiotherapy based on weekly cisplatin application with external radiotherapy was applied to big tumors at early stage or locally advanced tumors [Citation31–33]. However, recent evidence [Citation34,Citation35] demonstrates its applicability to all women and a benefit of non-platinum-based chemoradiotherapy.
Our finding of a particularly strong improvement in survival for the age groups 55–64 and 65–74 years may reflect increasing adoption of the concurrent chemoradiotherapy on the population level in these age groups, but possibly not yet among the “oldest old”. To our knowledge, at population level, there is no data specifically focusing on this issue and little is known about the effect of the adoption of the concurrent chemoradiotherapy on survival at population level. In a population-based cohort study from Ontario, Canada, the elevation from 10% (prior to 1999) to 60% (1999–2001) in proportion of adoption of concurrent chemoradiotherapy was demonstrated to go along with significant improvement in three-year overall survival [Citation36]. A retrospective analysis of clinical trial data showed that for locally advanced cancer, patients aged 55 years and older with concurrent chemoradiotherapy can achieve similar progression-free and overall survivals as younger patients [Citation37]. The poor prognosis of cervical cancer in the oldest age group in our study might also be partly attributable to low coverage of screening among older women [Citation3,Citation38]. Additionally comorbidities and less access to therapeutic innovations in older women could be additional reasons [Citation39].
We observed a higher survival in patients with squamous cell cancer than in patients with adenocarcinomas (66% and 63%, respectively), in line with most studies [Citation20,Citation29,Citation40]. It is well known that oncogenic types of HPV play a key role in the etiology of cervical cancer [Citation41–43] and, HPV 16 presents predominantly in squamous cell carcinomas (51%), while HPV 18 predominates in adenocarcinomas (56%) [Citation43]. Given that HPV genotypes are independent prognostic factors of cervical cancer in several studies [Citation44,Citation45], it is plausible to assume that different profiles of HPV genotypes in histologic subtypes of cervical cancer may contribute to the variation in survival by histologic subtypes.
In agreement with previous studies [Citation20,Citation29], we found a strong gradient in survival by stage, which underlines the key role of early detection and timely treatment of cervical cancer for reducing both incidence and mortality from cervical cancer [Citation2].
A major strength of our study lies in a large sample size. This is the first comprehensive population-based study from Germany providing survival estimates of cervical cancer, using a pooled German national dataset with a large sample size (15 685 cases) and covering a population of 33 million people (40% of the German population). Furthermore, this study provided most up-to-date and comprehensive survival estimates of cervical cancer in the early 21st century, using the techniques of standard and model-based period analysis. Limitations are mainly related to lack of information on screening, diagnostic procedures and treatment. Also, stage information was available for 51% of cases only, precluding joint stratification by stage and other factors, such as histology, in time trend analyses. Furthermore, we hesitated to impute the stage variables due to the critically large amount of missing information [Citation46]. The results concerning stage should be interpreted with caution due to the substantial proportion of missing data for stage.
In summary, in this first comprehensive population-based study from Germany we demonstrate that prognosis of cervical cancer strongly varied by age, histology and stage. In addition, for the recent five-year period under investigation, a statistically significant improvement in overall five-year RS estimates (4.7 percent units) was seen. The improvement was most pronounced in the age range 55–74 years, possibly due to increasing adoption of concurrent chemoradiotherapy at the population level.
http://informahealthcare.com/doi/abs/10.3109/0284186X.2012.708105
Download PDF (32.5 KB)Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Members of the GEKID Cancer Survival Working Group: Karla Geiss, Martin Meyer (Cancer Registry of Bavaria), Andrea Eberle, Sabine Luttmann (Cancer Registry of Bremen), Roland Stabenow (Cancer Registry of Berlin and the New Federal States), Stefan Hentschel, Alice Nennecke (Hamburg Cancer Registry), Joachim Kieschke, Eunice Sirri (Cancer Registry of Lower Saxony), Bernd Holleczek (Saarland Cancer Registry), Katharina Emrich (Cancer Registry of Rhineland-Palatinate), Hiltraud Kajüter, Volkmar Mattauch (Cancer Registry of North Rhine-Westphalia), Alexander Katalinic (Cancer Registry of Schleswig-Holstein), Klaus Kraywinkel (Robert Koch Institute, Berlin), Hermann Brenner, Lina Jansen, Adam Gondos (DKFZ). This study was funded by German Cancer Aid (Deutsche Krebshilfe), grant no. 108257. The sponsor had no role in the study design, collection, analysis, or interpretation of data.
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